Although the immune system was once thought to function autonomously, there is now compelling evidence that psychological stress-induced, neuroendocrine-derived peptides and hormones play a key role in regulating numerous aspects of immunity. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of corticosterone/cortisol is a major mediator of stress-induced effects on immune function and is modulated, in part, by the opioid receptor. However, the genetic factors which regulate HPA axis activity have not yet been elucidated. A relatively common single nucleotide functional polymorphism (SNP) has recently been identified in the human opioid receptor gene (OPRM1; A118G nucleotide exchange; asparagine-to-aspartic acid change at amino acid residue 40). Interestingly, the distribution of this SNP is closely aligned along specific races and ethnicities and its presence has recently been associated with increased sensitivity to pain and a reduced analgesic response to opioids. In addition, individuals having at least one copy of this A118G allele exhibit increased basal levels of cortisol and a decreased cortisol response to a behavioral stressor. How these alterations in the levels of cortisol affect immunity to infectious pathogens and the development of protective immunity in response to vaccinations remains to be determined. The studies described herein combine the interests and expertise of a basic scientist with research roots in stress-associated neuroimmunology and a clinician-scientist with interest and expertise in genetic-stress interactions, to test the hypothesis that the A118G polymorphism alters the HPA axis response to acute and chronic psychological stress which, in turn, affects the magnitude of the cytotoxic T lymphocyte (CTL)-based adaptive immune response to herpes simplex virus (HSV) infection. These studies will utilize a murine model of stress and measurements of HSV-specific immunity with which these investigators have considerable experience. Such studies will provide a foundation for longer-term studies to determine the impact of this A118G SNP on the human neuroendocrine response to stress, innate and adaptive immunity, resistance to infectious pathogens, and the ability to respond to vaccinations. The results from these studies may, in turn, promote the utilization of interventional strategies to minimize the levels of stress in individuals who harbor at least one copy of the A118G allele and who may not be able to effectively verbalize their feelings of psychological and physical stress and their need for stress-reduction intervention. PUBLIC HEALTH RELEVANCE: These studies will begin to determine how very small changes in gene composition control the hormones that are produced during psychological stress and how these hormones affect one's natural immunity to infectious diseases and the immunity that is afforded by vaccination. Such studies could ultimately result in treatments that are designed to reduce the impact of stress on immunity and/or reduce the stress itself, particularly in those individuals whose genetic composition results in a detrimental suppression immune function.